Huntington's disease (HD) is an inherited neurodegenerative disease affecting 30,000 people in the United States. HD is caused by expansion of a CAG trinucleotide repeat in the first exon of the huntingtin (HTT) gene and results in translation of a protein that contains an enlarged CAG- encoded polyglutamine (polyQ) tract at the N-terminus. HD is characterized by progressive loss of neurons in the cerebral cortex and striatum during aging. This neurodegeneration results in neurocognitive decline, personality changes, chorea (involuntary movement), dementia and death. Toxicity of mutant HTT protein is caused by production of protein fragments by several protease families including caspases, calpains and matrix metalloproteinases (protein degrading enzymes). These fragments begin to accumulate and aggregate in neurons during aging and lead to the mutant HTT toxicity that causes HD. The objective of this project is to understand which fragments of HTT are the most toxic and what causes this toxicity. To answer these questions, we generated five transgenic mouse models that express an individual HTT proteolysis fragment to characterize the contribution of each proteolysis fragment to HD-related neurodegeneration. We have identified two fragments that cause accelerated neurodegeneration and have accumulated data suggesting that this neurodegeneration is caused by accumulation of HTT fragments in protein complexes that contain wild-type HTT. The aims of this project are to identify proteins that are lost or added to the wild-type HTT complex as HTT fragments accumulate in it, then to test these proteins for their role in HTT fragments' toxicity. Our long-term goal is to identify proteins that work with HTT fragments to cause the neurotoxicity in HD. Understanding which proteins work with HTT fragments to cause toxicity will give us valuable insights into the mechanisms of HD and may be relevant for other aging- related neurodegenerative diseases involving toxic protein accumulation including Alzheimer's disease (AD), Parkinson's disease (PD) and the eight other known polyQ diseases. Finally, identification of novel proteins and pathways involved in neurotoxicity in HD will enable us to develop new drugs to slow or stop progression of neurodegeneration in HD patients.